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Abstract This phase III trial aimed to compare ARX788, a site-specific, construct-homogeneous antibody-drug conjugate, with lapatinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) who had progressed on one line of trastuzumab based regimen. Eligible patients were randomized (1:1) to receive ARX788 (1.5 mg/kg, IV, Q3W) or lapatinib plus capecitabine (LC: lapatinib 1250 mg QD; capecitabine 1000 mg/m2 BID, days 1–14, Q3W) and stratified by prior chemotherapy lines (0-1 versus >1) and visceral metastasis (yes versus no). The primary outcome was progression-free survival (PFS) assessed by a blinded independent central review (BICR). A total of 441 patients were randomly assigned to receive either ARX788 (n = 221) or LC (n = 220). The median PFS was 11.3 (95% confidence interval [CI], 8.4–13.8) months with ARX788 compared with 8.2 (95% CI, 6.9–8.7) months with LC, as per BICR (hazard ratio [HR] 0.64, p = 0.0006). Frequencies of treatment-related adverse events (TRAEs) of any grade were 98.6% and 99.1% for ARX788 and LC, respectively. Grade ≥3 TRAEs were 41.4% and 40.0%, respectively, the most common adverse events were blurred vision (12.3%), dry eye (9.1%), keratopathy (5.9%), and interstitial lung disease (ILD, 5.9%) with ARX788; hand-foot syndrome (18.1%) and hypokalemia (5.1%) with LC; all the hematological and gastrointestinal events of grade ≥3 with ARX788 were less than 3%. Six treatment-related deaths occurred, with three cases possibly related to ILD. ARX788 significantly improved PFS compared with LC in patients with HER2-positive ABC with a distinct toxicity profile, supporting it as a potential treatment option.

Abstract Non-nucleotide stimulators of interferon gene (STING) agonists hold promise as immunotherapeutic agents for postsurgical adjuvant treatment of tumors. However, their limited effect duration hampers therapeutic effectiveness, necessitating prolonged administration of multiple doses that heightens infection risk and impacts patient compliance. Here, we develop an implantable dual-drug depot in a sandwich-like configuration, with a non-nucleotide STING agonist (MSA-2) in the outer layers of 3D-printed scaffolds and an immunogenic apoptosis inducer (doxorubicin, DOX) in the inner layer of electrospun fibers. We discover that MSA-2 can elicit endoplasmic reticulum stress-mediated and general immunogenic apoptosis of cancer cells. The stimulations with tumor-associated antigens and damage-associated molecular patterns from cancer cells, along with proinflammatory factors secreted by matured dendritic cells and M1-polarized macrophages, can depolymerize intracellular microtubules guiding activated STING trafficking towards lysosomes for degradation. Collectively, the dual-drug depots can initiate a long-lasting cascaded immunotherapy and chemotherapy, suppressing postsurgical tumor recurrence and metastasis.

Abstract Background Patients suffer from esophageal squamous cell carcinoma (ESCC), which is the ninth highly aggressive malignancy. Tumor-infiltrating immune cells (TIIC) exert as major component of the tumor microenvironment (TME), showing possible prognostic value in ESCC. Methods Transcriptome data and scRNA-seq data of ESCC samples were extracted from the GEO and TCGA databases. Tissue Specific Index (TSI) was defined to identify potential TIIC-RNAs from the TME. Twenty machine learning algorithms were further applied to evaluate the prognostic efficacy of TIIC signature score. Gene colocalization analysis was performed. Differences in CNV on chromosomes and SNP sites of prognostic model genes were calculated. Results The most reliable model of TIIC signature score was developed based on three prognostic TIIC-RNAs. It showed a higher C-index than any other reported prognostic models. ESCC patients with high TIIC signature score showed poorer survival outcomes than low TIIC signature score. The activity of most immune cells decreased with the increase of TIIC score. TIIC signature score showed difference in the expression levels and methylation levels of DEGs. There was also significant different correlation with the degree of CNV amplification and CNV deletion of the immune checkpoint genes. Gene colocalization analysis showed two prognostic model genes (ATP6V0E1 and BIRC2). MR analysis found that rs148710154 and rs75146099 SNP sites of TIIC-RNA gene had a significant correlation between them gastro-oesophageal reflux and ESCC. Conclusion TIIC signature score was the first time developed which provided a novel strategy and guidance for the prognosis and immunotherapy of ESCC. It also gave the evidence in the important role of immune cells from the TME in the treatment of cancers.

BackgroundThe use of highly active antiretroviral therapy has transformed AIDS into a chronic infectious disease, but issues of chronic inflammation and immune system activation persist. Modulating the gut microbiome of patients may improve this situation, yet the specific association mechanisms between HIV and the gut microbiome remain unclear. This study aims to explore the research hotspots and trends of the HIV and the gut microbiome, providing direction for future research.MethodsWe conducted a search of the Web of Science Core Collection database up to April 30, 2024 to retrieve articles related to the relationship between the HIV and the gut microbiome. The scientific achievements and research frontiers in this field were analyzed using CiteSpace, VOSviewer, and Bibliometrix statistical software.ResultsAs of April 30, 2024, a total of 379 articles met the inclusion criteria. The number of publications in this field peaked in 2023, and the number of articles published after 2020 declined. The country with the highest number of publications was the United States (184 articles), and the institution with the most publications was the University of Colorado (USA) (21 articles). The author with the most publications was Routy Jean-Pierre (Canada) (14 articles). High-frequency keywords, aside from the key terms, included “HIV,” “inflammation,” “immune activation,” “gut microbiota,” and “translocation.” Keyword burst results indicated that short-chain fatty acids, T cells and obesity might become the focus of future research.ConclusionThe research hotspots in this field should prioritize examining the role of the primary gut microbiome metabolite, short-chain fatty acids, in reducing immune system activation and inflammation. Another emerging area of interest could be the investigation into the annual increase in obesity rates within this field. Furthermore, understanding the metabolic mechanisms of short-chain fatty acids in T cells is essential. Additionally, multi-omics analysis holds potential.

More than 90% of deaths due to breast cancer (BC) are due to metastasis-related complications, with invasive ductal carcinoma (IDC) of the breast being the most common pathologic type of breast cancer and highly susceptible to metastasis to distant organs. BC patients who develop cancer metastases are more likely to have a poor prognosis and poor quality of life, so it is extremely important to recognize and diagnose whether distant metastases have occurred in IDC as early as possible. In this study, we develop a non-invasive breast cancer classification system for detecting cancer metastasis. We used Anaconda-Jupyter notebooks to develop various Python programming modules for text mining, data processing, and machine learning (ML) methods. A risk prediction model was constructed based on four algorithms: Random Forest, XGBoost, Logistic Regression, and SVM. Additionally, we developed a hybrid model based on a voting mechanism using these four algorithms as the base models. The models were compared and evaluated by the following metrics: accuracy, precision, recall, F1-score, and area under the ROC curve (AUC) values. The experimental results show that the hybrid model based on the voting mechanism exhibits the best prediction performance (accuracy: 0.867, precision: 0.929, recall: 0.805, F1-score: 0.856, AUC: 0.94). This stable risk prediction model provides a valuable reference support for doctors in assessing and diagnosing the risk of IDC hematogenous metastasis. It also improves the work efficiency of doctors and strives to provide patients with increased chances of survival.

To provide autonomous and accurate time service for deep space missions, a pulsar observation–based timekeeping method is documented in this paper, which utilizes pulsars as the time information source. Firstly, the pulsar observation noise is remodeled as the combination of the Gaussian noise and colored noise, and the detailed expression of the colored noise is presented in the paper. An improved Grey model (GM) is proposed to describe the onboard clock evolution, which models the grey action quantity as a time-varying coefficient and attenuates the dependence of the model on the initial state. On the basis of the modified observation noise model and GM, an unscented Kalman filtering (UKF) is adopted to estimate the onboard clock error. Numerical experiments are conducted to analyze the validity of the proposed method and the impact of spacecraft positioning error and pulsar selection on the proposed method. The proposed method offers an autonomous solution for onboard timekeeping in deep space missions.

Pulmonary arterial hypertension (PAH) is a malignant cardiovascular disease with a complex etiology, in which several types of cells play important roles. Sex differences in disease susceptibility and survival have been observed in PAH patients, but few studies have analyzed the effect of changes in cell type and number on sex differences in PAH at the single-cell level. In this study, we performed a series of analyses on GSE169471 and GSE228644 datasets and found significant changes in the ratio of several types of cells in male PAH lung tissues. Surprisingly, we found that the ratio of macrophages in male PAH samples was 7 times higher than that in females. Consistently, the ratio of M1 macrophages was also significantly increased in male PAH samples. The different expression genes (DEGs) in macrophages were mainly involved in the ribosome pathway, which is closely related to cell proliferation. Inhibition of ribosomal protein L39 (RPL39), a core gene in the ribosome pathway, can inhibit macrophage proliferation and attenuate the sex differences in PAH. In conclusion, our study suggests that ribosome pathway–associated cell proliferation of macrophages might be associated with sex differences in PAH.

Summary: Avian coccidiosis is a widespread intestinal disease found in poultry that causes substantial economic losses. To extensively investigate the molecular mechanism of drug resistance in Eimeria tenella, we analyzed the sporozoites and second-generation merozoites of drug-sensitive (DS), diclazuril-resistant (DZR) strain, and salinomycin-resistant (SMR) strains of E. tenella through transcriptome sequencing. Whole genome sequencing analyses were performed on resistant strains at different concentrations—11 sensitive strains, 16 field diclazuril-resistant strains, and 15 field salinomycin-resistant strains of E. tenella. Co-analysis indicated that the ABC transporter protein showed differential expression and base mutations in the two resistant strains compared with the DS strain. KEGG pathway analysis demonstrated that the expression of pABAS and HPPK-DHPS, which are associated with the folate biosynthetic pathway, showed downregulation only in the DZR strain with respect to the DS strain. Several key enzymes in the glycolytic pathway were differentially expressed between DS and SMR strains.

Alternanthera philoxeroides (Mart.) Griseb is a well-known invasive plant species worldwide. Cinnamomum camphora (L.) Presl. is a plant species that is rich in allelopathic substances which can impede the growth of many other plants. In this study, the allelopathic effects of C. camphora on the growth and development, and physiological-biochemical characteristics of A. philoxeroides were investigated. The findings revealed that the leaves of C. camphora exhibited the capability to suppress the asexual reproduction of A. philoxeroides. The addition of C. camphora leaves resulted in inhibition of the fresh weight, stem length, and stem node number of A. philoxeroides new stems, with the strength of inhibition increasing in proportion to the quantity of C. camphora leaves added. Furthermore, the inhibitory effect of C. camphora leaves on A. philoxeroides was significantly amplified under high temperatures (≥ 30°C). Two allelochemicals had strong inhibitory effects on the vegetative reproduction of A. philoxeroides. The inhibition intensities were all up to 100 % on stem vegetative propagation, were 90.40 % and 100 % on root vegetative propagation from camphor and linalool, respectively. Physiological-biochemical analyses of roots indicated that the two allelochemicals promoted the accumulation of hydrogen peroxide and MDA, disrupting the balance of antioxidant enzyme systems. The two allelochemicals had a strong inhibitory effect on CAT activity and a strong promoting effect on POD activity. The effect on SOD activity was greatly affected by the type and concentration of allelochemicals. Moreover, the two allelochemicals significantly inhibited the accumulation of osmotic regulating substance. The contents of soluble sugar, soluble protein, and proline were significantly down-regulated. In summary, the allelochemicals from C. camphora induced damage to biological membranes, disrupting antioxidant enzyme systems and inhibiting osmoregulation. This resulted in the retardation of growth, development, and potential mortality of A. philoxeroides. These findings would contribute to the knowledge base for A. philoxeroides prevention and control, and enrich the understanding of C. camphora allelopathic substances.

N6-methyladenosine (m6A) is the most prevalent internal chemical modification in eukaryotic messenger RNA (mRNA), significantly impacting its lifecycle through dynamic and reversible processes involving methyltransferase, demethylase, and binding proteins. These processes regulate mRNA stability, splicing, nuclear export, translation, and degradation. Programmed cell death (PCD), a tightly controlled process encompassing apoptosis, pyroptosis, ferroptosis, autophagy, and necroptosis, plays a crucial role in maintaining cellular homeostasis, tissue development, and function. Recently, m6A modification has emerged as a significant research area due to its role in regulating PCD and its implications in cardiovascular diseases (CVDs). In this review, we delve into the intricate relationship between various PCD types and m6A modification, emphasizing their pivotal roles in the initiation and progression of CVDs such as myocardial ischemia-reperfusion (I/R), atherosclerosis (AS), pulmonary hypertension (PH), cardiomyopathy, doxorubicin (Dox)-induced cardiotoxicity (DIC), heart failure (HF), and myocardial infarction (MI). Our findings underscore the potential of elucidating the roles of m6A and PCD in CVD to pave new pathways for prevention and treatment strategies.